The recent in vivo appearance of acyclovir-resistant strains of herpes simplex virus stresses the need for new therapeutic agents to combat this common virus. Topical interferon preparations may help fill this void. In the present study dimethyl sulfoxide was combined with alpha-interferon in an ointment base to increase percutaneous penetration. In this double-blind, placebo-controlled trial, patients with recurrent genital herpes simplex using the topical alpha-interferon preparation had a more rapid cessation of viral shedding when compared to the placebo group (66% culture negative on day 1 vs. 25% of placebo patients; p less than 0.02). In the 90-day post-treatment period, interferon-treated patients had fewer recurrences than their placebo-treated counterparts (1.18 vs. 2.25). This reduction while not statistically significant was encouraging (p less than 0.10).